Dysregulation of intracellular calcium handling is a fundamental and early manifestation of sarcomere mutations. Animal models of HCM demonstrated abnormal Ca2+ cycling prior to the development of myocyte disarray or hypertrophy. Manipulation of intracellular Ca2+ handling in young, pre-hypertrophic mice with HCM via administration of the L-type Ca2+ channel blocker, diltiazem, attenuated the degree of hypertrophic remodeling and diminished the phenotypic manifestations of sarcomere mutations. Notably, if treatment was initiated later in life, after LVH was allowed to develop, there was no significant effect. Although this strategy has not yet been tested in humans, diltiazem is a commonly-used medication with a long track record of safety and tolerability.